APOBEC affects tumor evolution and age at onset of lung cancer in smokers
Abstract
Abstract Most solid tumors harbor somatic mutations attributed to off-target activities of APOBEC3A (A3A) and/or APOBEC3B (A3B). However, how APOBEC3A/B enzymes affect tumor evolution in the presence of exogenous mutagenic processes is largely unknown. Here, multi-omics profiling of 309 lung cancers from smokers identifies two subtypes defined by low (LAS) and high (HAS) APOBEC mutagenesis. LAS are enriched for A3B-like mutagenesis and KRAS mutations; HAS for A3A-like mutagenesis and TP53 mutations. Compared to LAS, HAS have older age at onset and high proportions of newly generated progenitor-like cells likely due to the combined tobacco smoking- and APOBEC3A-associated DNA damage and apoptosis. Consistently, HAS exhibit high expression of pulmonary healing signaling pathway, stemness markers, distal cell-of-origin, more neoantigens, slower clonal expansion, but no smoking-associated genomic/epigenomic changes. With validation in 184 lung tumor samples, these findings show how heterogeneity in mutational burden across co-occurring mutational processes and cell types contributes to tumor development.
Article Details
Authors (31)
Tongwu Zhang
Jian Sang
Phuc H. Hoang
Wei Zhao
Jennifer Rosenbaum
Kofi Ennu Johnson
Leszek J. Klimczak
John McElderry
Alyssa Klein
Christopher Wirth
Erik N. Bergstrom
Marcos Díaz-Gay
Raviteja Vangara
Frank Colon-Matos
Amy Hutchinson
Scott M. Lawrence
Nathan Cole
Bin Zhu
Teresa M. Przytycka
Jianxin Shi
Neil E. Caporaso
Robert Homer
Angela C. Pesatori
Dario Consonni
Marcin Imielinski
Stephen J. Chanock
David C. Wedge
Dmitry A. Gordenin
Ludmil B. Alexandrov
Reuben S. Harris
Maria Teresa Landi